Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia

Despite improvements in therapies targeted at reducing disease burden, coronary
artery disease (CAD) continues to afflict >16 million US adults, accounting for
more than 1/3 of all deaths and responsible for 1.2 million hospitalizations
annually. Coronary revascularization remains a mainstay of treatment for CAD,
with >1.2 million percutaneous interventions and 440,000 coronary artery bypass
surgeries performed annually in the US, and occurring in more than half of
hospitalizations for CAD.
In clinical practice, revascularization is often performed on an ad hoc basis
from semi-quantitative measures of percent luminal diameter narrowing of the
artery visualized at the time of invasive coronary angiography (ICA). This
practice stems from the pioneering research of Gould et al. who elegantly
demonstrated the relationship between stenosis and ischemia*as determined by
myocardial blood flow (MBF) reserve*wherein flow to the myocardium is
compromised as the coronary luminal diameter progressively narrows. This
diminution in flow is most evident at hyperemic states and can begin as early
as 40% stenoses, with more predictable reductions in hyperemic coronary flow
for stenoses *70%. Yet the relationship between coronary stenosis and ischemia
is complex, with a multitude of ensuing studies demonstrating an unreliable
relationship between stenosis severity and reduced MBF. One contemporary
example of this was highlighted in the nuclear substudy of the Clinical
Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)
trial where*for patients with *70% stenosis*only 32% exhibited severe ischemia
and 40% manifested no or mild ischemia by myocardial perfusion scintigraphy.
This marked disparity suggests that, even in the setting of severe coronary
stenosis, other factors are operative in the regulation of MBF.
Numerous non-invasive imaging tests have thus emerged for physiologic
assessment of CAD, including cardiac magnetic resonance and myocardial
perfusion scintigraphy by either single photon emission CT (SPECT) or positron
emission tomography (PET). These modalities identify stress-induced regional
myocardial perfusion defects as a surrogate for ischemia, and serve to identify
individuals who may have severe coronary stenoses. Among the non-invasive
stress modalities, MPI is performed most commonly, comprising 90% of the more
than 10 million stress imaging test performed in the US annually. MPI by SPECT
or PET determines extent, severity and reversibility of myocardial ischemia
with high performance at a per-patient level. In pooled analyses, the
sensitivity and specificity of MPI to diagnose coronary stenosis is 85-90% and
70-75%, respectively. Further, the prognostic value of MPI is unsurpassed by
other non-invasive tests. Despite its high reported diagnostic performance, the
*real world* accuracy of MPI is less sanguine.
CT of >64-detector rows has emerged as a promising non-invasive option for
coronary angiography, with significant advances in CT temporal resolution and
volume coverage now allowing for acquisition of virtually motion-free images at
isotropic spatial resolution between 500-750 *m. In the first prospective
multicenter study of its kind, CT was performed on 230 patients prior to ICA
irrespective of baseline coronary calcium score, body mass index or heart rate.
For severe stenosis, CT demonstrated a sensitivity, specificity, positive
predictive value (PPV) and negative predictive value (NPV) of 94%, 83%, 48%,
and 99%, respectively, compared to ICA. While CT excels for discriminating
stenosis, stenosis by CT for identifying ischemia is poor. At present, the
*gold* standard assessment of the hemodynamic significance of coronary stenoses
is invasive fractional flow reserve (FFR). Recent advances in computational
fluid dynamics (CFD) now enable calculation of coronary flow and pressure
fields from anatomic image data. Applied to CT, these technologies enable
calculation of FFR (the ratio of maximal myocardial blood flow through a
diseased artery to the blood flow in the hypothetical case that the artery was
normal) without additional imaging or administration of additional medications
at the time of CT.
Numerous in vivo anatomic imaging techniques exist that allow for visualization
of atherosclerotic plaque characteristics (APCs) of CAD beyond stenosis
severity. Of these, intravascular ultrasound (IVUS) has been most widely
employed. IVUS-visualized APCs distinguish culprit lesions implicated in acute
coronary events.

The present proposal seeks to integrate the entirety of anatomic and
physiologic information measurable by CT to optimize the precise identification
of coronary vessels that manifest ischemia. These determinations will take
place in the largest cohort of patients undergoing CT, MPI, ICA and FFR, and on
a background of comprehensive core laboratory-interpreted image assessment and
clinical data collection; thus rendering this proposal the most thorough effort
to date to determine the utility of a novel integrated anatomic-physiologic
approach to diagnosing vessel-specific ischemia. In doing so, this proposal
aims to establish the rationale for a novel diagnostic paradigm that is more
accurate than conventional stress imaging testing for not only identifying
patients who manifest ischemia but also pinpointing the coronary lesions that
are the cause; thus, allowing for better selection of individuals for
revascularization and eliminating unnecessary invasive procedures.
To date, the relative performance of traditional stress imaging testing
compared to the entirety of information proffered by CT (e.g., FFRCT and APCs)
has not been assessed compared to an unbiased gold standard. The study proposed
herein will directly address this unmet need.

The CREDENCE trial will be a prospective multicenter cross-sectional study of
618 individuals (n=309 [derivation cohort]; n=309 [validation cohort]) who will
undergo MPI, CT, ICA and FFR. For the purposes of the study, either MPI or CT
will have been performed for clinical purposes, with the other test being
performed as part of trial procedure. Study analyses will focus on the
diagnostic performance of the information derived by MPI versus CT against an
invasive gold standard of ICA + FFR for an endpoint of vessel
territory-specific ischemia. In keeping with prior studies, vessel territories
will be comprised of the left anterior descending artery [LAD] (and diagonal
branches), the left circumflex artery [LCx] (and obtuse marginal branches) and
the right coronary artery [RCA] (and posterolateral branch and posterior
descending artery).
The targeted population will be those for whom CT and MPI testing confer the
largest potential benefit; that is, for those with suspected CAD who are being
referred for non-emergent clinically indicated ICA based upon an imaging study
(either MPI or CT). The study is considered non-significant risk because all
subjects will undergo clinically-indicated ICA as planned, with FFR performed
in vessel territories with >50% stenosis. Additional study procedures will
include only one additional non-invasive procedure with a very low rate of
complications (<1%).

MPI can be performed by a variety of methods, including SPECT, PET and CMR.
These test are routinely and commonly employed for evaluation of patients with
suspected CAD in the clinical setting. Risks associated with stress testing are
very low. For pharmacologic stress testing using adenosine, there may be a low
incidence of wheezing or shortness of breath. These symptoms may require
treatment in the low frequency of patients for which they occur, but most
commonly dissipate very quickly after cessation of adenosine. MPI performed by
SPECT or PET exposes patients to small amounts of radiation. For the CREDENCE
study, the MPIs will comprise the majority of tests that have been performed
for clinical purposes and will thus not represent any additional radiation
exposure. The estimated radiation dose for the SPECT or PET examination is
estimated to range between 3-12 milliSieverts (mSv). In comparison, the
estimated annual radiation exposure from background radiation is approximately
3 mSv for an adult individual living at sea level.
CCTA exposes patients to small amounts of ionizing radiation, the estimated
effective biological radiation dose for the CCTA examination is estimated to
range between 2-8 mSv. In comparison, the average yearly effective dose of
natural background radiation is ~3 mSv, the allowed annual exposure of
radiation workers is 50 mSv, the allowed exposure in five years is 100 mSv.
CCTA performance necessitates use of iodinated contrast. Minor reactions to
x-ray contrast material can occur such as itching or hives with an incidence of
approximately 1 in 200 subjects. These reactions are treated with intravenous
Benadryl (antihistamine). More severe reactions that are very infrequent
include hypotension, laryngospasm and bronchospasm. The incidence of these
reactions is estimated at about 1 in 5,000 and is treated with intravenous
epinephrine. Contrast-induced nephropathy (CIN) is expected to be a very rare
event among this patient population because patients with already impaired
renal function will not be enrolled.
All ICAs will be performed as part of routine clinical care. No ICA will be
performed for non-clinically indicated research purposes. Cardiac
catheterization procedures, including ICA, carry a very low risk of
complications that is less than 1% for ICA. If FFR is not performed as a part
of clinical care, it will be done for the purpose of this research study. FFR
is a short and painless procedure that will take approximately 10-15 minutes.
FFR requires the use of a very thin wire to measure the pressures in the
coronary arteries. This procedure is very safe but can result in similar
potential complications of ICA. Risk of coronary dissection from FFR is 0.6%.
In addition, FFR measurements require the use of intravenous adenosine. The
administration of adenosine is routine in clinical practice and in the
performance of FFR. Side effects of adenosine, however, include facial
flushing, a temporary rash on the chest, lightheadedness, diaphoresis, nausea
or a metallic taste after administration. These symptoms are almost always
temporary, and generally last less than a minute.